Ischemic Preconditioning in the Intact Rat Heart Is Mediated by δ 1 - But Not μ- or κ-Opioid Receptors

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Abstract
Background—Our laboratory has previously shown that δ-opioid receptors are involved in the cardioprotective effect of ischemic preconditioning in the rat heart. However, this class of receptors consists of two subtypes, δ1 and δ2, and μ- or κ-opioid receptors may also exist in the heart. Therefore, the purpose of the present study was to test the hypothesis that ischemic preconditioning is mediated through stimulation of one or both δ-opioid receptor subtypes. Methods and Results—Anesthetized, open chest, male Wistar rats were assigned to 1 of 14 groups. All animals were subjected to 30 minutes of occlusion and 2 hours of reperfusion. Ischemic preconditioning was elicited by three 5-minute occlusion periods interspersed with 5 minutes of reperfusion. Two doses of 7-benzylidenenaltrexone (BNTX; 1 and 3 mg/kg IV), a selective δ1-opioid receptor antagonist, or naltriben (NTB; 1 and 3 mg/kg IV), a selective δ2-opioid receptor antagonist, were given before ischemic preconditioning. To test for a role of μ-opioid receptors, rats were pretreated with β-funaltrexamine (β-FNA; 15 mg/kg SC), an irreversible μ-opioid receptor antagonist, 24 hours before ischemic preconditioning or given the μ-opioid receptor agonist D-Ala,2N-Me-Phe,4glycerol5-enkephalin (DAMGO) as three 5-minute infusions (1, 10, and 100 μg/kg per infusion IV, respectively) interspersed with 5-minute drug-free periods before the prolonged ischemic and reperfusion periods (lowDAMGO, medDAMGO, and hiDAMGO, respectively). The involvement of κ-opioid receptors was tested by administering one of two doses of nor-binaltorphimine (nor-BNI; 1 and 5 mg/kg IV) before ischemic preconditioning. Infarct size (IS) as a percent of the area at risk (AAR) was measured by triphenyltetrazolium stain. Ischemic preconditioning markedly reduced IS/AAR (14±4%, P<.05) compared with control (55±4%). NTB, β-FNA, and nor-BNI were unable to block the cardioprotective effect of ischemic preconditioning. In addition, DAMGO had no effect on IS/AAR. However, the high dose of BNTX (3 mg/kg IV) significantly attenuated the cardioprotective effect of ischemic preconditioning (39±5%; P<.05 versus control and ischemic preconditioning). Conclusions—These results indicate that δ1-opioid receptors play an important role in the cardioprotective effect of ischemic preconditioning in the rat heart.